The level of LDL in plasma is the major determinantof the risk of vascular disease and lowering the level ofLDL diminishes that risk, both in those with and thosewithout symptomatic vascular disease [1–4]. Fully un-derstanding the factors that govern the concentration ofplasma LDL is, therefore, one of our most importantchallenges. Since its enunciation [5,6], the LDL receptorparadigm has dominated thinking in this area. In brief,it states that the major determinant of the concentra-tion of LDL is the rate at which LDL particles arecleared from plasma and that the rate of LDL clearancefrom plasma is determined by the activity of hepaticLDL receptors.The LDL receptor paradigm stipulates that choles-terol which has entered the cell via the LDL pathwayproduces three coordinated and concurrent events: de-creased cholesterol synthesis, decreased LDL receptorsynthesis, and increased cholesterol ester synthesis; allthree of which act to ensure the level of free cholesterolwithin the cell remains within the narrow limits neces-sary for normal membrane function and normal cellularfunction. On the other hand, LDL entering the cell byany non-LDL receptor pathway such as the scavengerreceptor will not elicit these self-limiting responses andaccordingly will lead to continuing unregulated accu-mulation of cholesterol within the cell. Thus one routeleads to synchronous self-correcting and therefore nor-mal responses, the other to progressive deviation anddisease. The LDL pathway is perhaps the best-knownexpression of biologic homeostasis in modern times.Two human metabolic disorders, familial hyperc-holesterolemia (FH) [7] and the defective apoB100 syn-drome [8], each of which has been explicitly defined atthe molecular level, testify unambiguously to the criticalbiologic importance of the LDL pathway for the hu-man organism. In the first, the LDL receptor is abnor-mal while in the second, the ligand for the LDLreceptor, apoB100, is abnormal. In both disorders, theclearance from plasma of LDL through the LDL path-way is markedly reduced, and consequently, in both,the levels of LDL are markedly elevated, as is the riskof coronary disease. The LDL receptor paradigmwould seem secure, and if it is, there is no need tosearch further to understand the regulation of plasmaLDL. But is it?Five years ago, Fisher, Zech and Stacpoole pointedout certain inconsistencies with the LDL receptorparadigm [9]. They noted that in WHHL rabbits, theanimal counterpart to FH [10], and in two humans withhomozygous (FH) [11], hepatic free cholesterol andcholesterol ester content were clearly although unex-pectedly increased. Moreover, in the WHHL rabbit,cholesterol synthesis is depressed [10] as is HMGCoAreductase activity and cholesterol synthesis in circulat-ing FH mononuclear cells [12]. These observations are,of course, inconsistent with the contention that onlycholesterol entering the cell via the LDL receptor canregulate internal cholesterol homeostasis [5,6].Since then, much more has been learned about theregulation of sterol balance within the hepatocyte, andby extension, within the organism as a whole. Thesedata lead to a model that is very different from theLDL paradigm: namely, that there is a second majordeterminant of the concentration of LDL in plasma —